This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for patients with Parkinson's disease, but the effects of this treatment on brain activity remain unknown. We therefore study the electrophysiologic and biochemical effects of DBS in normal and parkinsonian monkeys. Parkinsonism is induced by treatment with the dopaminergic neurotoxin MPTP. In the past funding period, we continued to study effects of STN stimulation in two normal animals. We found that STN stimulation produced effects on the activity of basal ganglia neurons that were more varied than previously appreciated. Although the effects of STN stimulation would be expected to be excitatory, firing rate changes in neurons that receive STN input varied substantially, ranging from inhibition to strong excitation. In many neurons the effects of short- and long-term stimulation differed, indicating the presence of adaptive changes. We also undertook a detailed analysis of firing pattern changes associated with STN stimulation. The stimulation-associated firing patterns differed between short- and long-term stimulation. We are currently completing microdialysis studies of the effects of STN stimulation on local levels of the inhibitory neurotransmitter GABA. We also repeated the same studies in two additional animals which were MPTP-treated. These experiments have been completed, but the results have not been analyzed. This part of the studies is crucial for a better understanding of the effects of electrical stimulation on basal ganglia activity in parkinsonian individuals. Insights into the mechanism of action of DBS in parkinsonism are needed to devise better stimulation protocols, may help to optimize placement of the stimulation probes in parkinsonian patients, and may help us to formulate rational pharmacologic approaches to maximize the beneficial effects of DBS and minimize its side effects.